Más contenido relacionado La actualidad más candente (20) Similar a fungi allergy -2014- (20) fungi allergy -2014-1. REVIEW ARTICLE
Fungi: the neglected allergenic sources
R. Crameri, M. Garbani, C. Rhyner & C. Huitema
Swiss Institute of Allergy and Asthma Research (SIAF), University of Z€urich, Davos, Switzerland
To cite this article: Crameri R, Garbani M, Rhyner C, Huitema C. Fungi: the neglected allergenic sources. Allergy 2014; 69: 176–185.
Keywords
allergy; fungi; immunoglobulin E; moulds;
recombinant allergens.
Correspondence
Prof. Reto Crameri, PhD, Department
Molecular Allergology, Swiss Institute of
Allergy and Asthma Research (SIAF), Obere
Strasse 22, CH-7270 Davos, Switzerland.
Tel.: +41 81 410 08 48
Fax: +41 81 410 08 40
E-mail: crameri@siaf.uzh.ch
Accepted for publication 14 October 2013
DOI:10.1111/all.12325
Edited by: Thomas Bieber
Abstract
Allergic diseases are considered the epidemics of the twentieth century estimated
to affect more than 30% of the population in industrialized countries with a still
increasing incidence. During the past two decades, the application of molecular
biology allowed cloning, production and characterization of hundreds of recombi-
nant allergens. In turn, knowledge about molecular, chemical and biologically
relevant allergens contributed to increase our understanding of the mechanisms
underlying IgE-mediated type I hypersensitivity reactions. It has been largely
demonstrated that fungi are potent sources of allergenic molecules covering a vast
variety of molecular structures including enzymes, toxins, cell wall components
and phylogenetically highly conserved cross-reactive proteins. Despite the large
knowledge accumulated and the compelling evidence for an involvement of fungal
allergens in the pathophysiology of allergic diseases, fungi as a prominent source
of allergens are still largely neglected in basic research as well as in clinical prac-
tice. This review aims to highlight the impact of fungal allergens with focus on
asthma and atopic dermatitis.
Allergy is a disease with many faces that can affect different
organs like upper and lower respiratory tract, eyes, intestinal
tract and the skin. Depending on the affected organ, allergic
symptoms manifest as allergic rhinitis (1), allergic asthma (2),
IgE-associated atopic dermatitis (3), food allergy (4) or insect
venom allergy (5), to mention only the most important ones.
The common hallmark of allergic diseases is a switch to the
production of allergen-specific IgE raised against normally
innocuous environmental allergens (6) that, in special cases,
might also cross-react with self-antigens (7, 8). At this
asymptomatic stage, the individual is sensitized to a given
allergenic source due to the presence of allergen-specific IgE
in serum, a condition also called ‘atopy’. Detection of aller-
gen-specific IgE is considered as a specific biomarker for the
atopic state in clinical practice, which allows in most cases a
linkage of a symptom to a particular allergen exposure (9).
Measurement of allergen-specific IgE antibodies in serum is
normally performed with fully automated devices (10) and
used to confirm sensitization to a particular allergen in sup-
port of a history-based clinical diagnosis of allergy or a
symptom-based suspicion. In sensitized (atopic) individuals,
however, re-exposure to the offending allergen induces cross-
linking of the high-affinity receptor FceRI-bound allergen-
specific IgE on effector cells and, thus, immediate release of
anaphylactogenic mediators (11). Although the mechanisms
leading to allergic reactions (12, 13) and the sources of
exposure are quite well known, our knowledge about the rep-
ertoire of molecular structures involved in the pathogenesis
of allergic reactions is still rudimentary (14) even if it is well
recognized that only a minor fraction of the myriad of pro-
teins to which humans are exposed provokes allergic reac-
tions. Bioinformatics analyses based on structural motifs (15)
and BLAST similarity search methods (16) involving 101 602
and 135 850 protein entries deposited in the Swiss-Prot data-
base predict 4093 (4%) and 4768 (3.5%) different potential
allergen structures, respectively. Therefore, one can assume
that the size of the allergen repertoire involved in eliciting
allergic symptoms is in the range of 5000 different structures
(14). The modest number of 753 allergenic proteins approved
by the World Health Organization and International Union
of Immunological Societies (WHO/IUIS) Allergen Nomencla-
ture Subcommittee (www.allergen.org) clearly shows our lack
of knowledge in this field. Allergenic structures can be found
in every species (Fig. 1), and the number of single allergens
characterized is unevenly distributed among the species rang-
ing from 1 for the phylum Cnidaria (sponges and jellyfish) to
252 for the Magnoliopsida trees (flowering plants). However,
this is rather due to the number of laboratories working with
the different allergenic sources than to the true presence of
allergenic structures among these species. Interestingly, the
most recent review dealing with nomenclature and structural
biology of allergens (17) states ‘most major allergens from
Allergy 69 (2014) 176–185 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd176
2. mites, animal dander, pollens, insects, and foods have been
cloned, and more than 40 three-dimensional allergen struc-
tures are in the Protein Database’ with fungal allergens con-
spicuously absent from this list. Fungal allergens are largely
neglected in the field of molecular allergology and also in
some reviews dealing with inhalant allergens and their role in
allergic airways disease (18) despite the predominant role
played by fungi in allergic asthma (19, 20).
Allergenic fungi and exposure to fungal allergens
Indoor and outdoor exposure to fungal components, includ-
ing spores, is a recognized triggering factor for respiratory
allergy and asthma (21), as well as for atopic dermatitis (22).
As highlighted in a pivotal review (23), among the over 100′
000 fungal species reported (24), only a few hundred have
been described as opportunistic pathogens (25) causing
human illness through three specific mechanisms: direct infec-
tion of the host, elicitation of deregulated immune responses
and toxic effects due to secondary metabolites (26). Among
these, about 80 mould genera have been shown to induce
type I allergies in atopic individuals (23). The most important
allergenic fungi belong to the genera Alternaria, Aspergillus
and Cladosporium (27), whereas members of the genera Can-
dida, Penicillium, Clavularia and others seem to be, with the
exception of the genus Malassezia in patients suffering from
atopic dermatitis (22, 28), less important as allergenic sources
(29).
The exact prevalence of fungal sensitization among the
general population is still unknown (27). This is not astonish-
ing as no reference standards for fungal extracts are available
to date even if dozens of commercial products are available
(30). However, it is well known that the use of commercial
extracts from different manufacturers can generate huge dif-
ferences in the outcome of in vitro or in vivo prevalence stud-
ies (31) due to the extreme variability of both content and
relative amounts of allergens in commercially available fungal
extracts (32). In conclusion, the marked differences in source
materials and manufacturing procedures used, the lack of
generally accepted potency assays and the great number of
potentially allergenic fungal species have hampered any
significant progress in fungal extract standardization. The
best estimates of fungal sensitization among allergic individu-
als come from a large skin prick test (SPT) survey on a
cohort of subjects with respiratory diseases conducted with
extracts from Alternaria, Aspergillus, Candida, Cladosporium,
Penicillium, Saccharomyces and Trichophyton and indicate a
prevalence of sensitization around 19% (29). The ranges of
prevalence of fungal sensitization for the general population,
atopic and asthmatic subjects, and mould-sensitized patients,
not claimed to be exhaustive, are reported in Table 1.
Clinical manifestations of fungal hypersensitivity
The clinical spectrum of hypersensitivity reactions elicited by
fungi is very broad and includes, besides IgE-mediated type I
allergy, reactions of types II, III and IV according to the old
definition of Coombs and Gell (33, 34). Although the classifi-
cation into types I to VI is widely used in clinical practice, it
should be mentioned that the reality is more complex because
frequently several mechanisms operate together in the patho-
genesis of hypersensitivity reactions, and this is especially
true for reactions to fungi. A brief classification of the differ-
ent types of hypersensitivity reactions with the mechanisms
Animalia
Arthropoda
27%
Animalia
Chordata
9%
Animalia
Nemata
2%
Fungi
16%
Plantae
Coniferopsida
2%
Plantae
Liliopsida
11%
Plantae
Magnoliosida
33%
Distribu on of characterized allergens by tree
Figure 1 Taxonomic distribution of the 753 allergens officially rec-
ognized by the World Health Organization and International Union
of Immunological Societies (WHO/IUIS) Allergen Nomenclature
Subcommittee (www.allergen.org). The WHO/IUIS allergen nomen-
clature database has been recently updated (138).
Table 1 Prevalence of mould allergy induced by different fungal species in% of the respective populations investigated
Genus General population Atopics* Asthmatics
Mould-allergic
individuals†
Alternaria 3.6–12.6 (20, 29) 3–14.6 (31, 139) 13.5–14.6 (140, 141) 66.1 (29)
Aspergillus 2.4 (29) 15–27.6 (22, 140) 5–21.3 (140, 141) 12.6 (29)
Candida 8.5 (29) 28,9 (22) 23.1 (141) 44.3 (29)
Cladosporium 2.5–2.9 (20, 46) 3–18.2 (31, 139) 15.9 (141) 13.1 (29)
Penicillium 1.5 (29) 7.3–13.1 (22, 139) 33 (142) 33 (142)
Trichophyton 1.9 (29) ND NA (29)* 10.2 (29)
*Individuals suffering from allergen-specific IgE-mediated sensitization against any allergenic source.
†Individuals sensitized to at least one mould. The prevalence of sensitization to single moulds in the subpopulation of subjects with multiple
fungal sensitizations might reach prevalences surpassing 80% for Alternaria (92.2%), Aspergillus (83.1%), Candida (89.6%) and Cladosporium
(84.4%) (29).
Allergy 69 (2014) 176–185 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 177
Crameri et al. Fungal allergens
3. involved in their pathogenesis is reported in Table 2. As this
review focuses on IgE-mediated type I allergic reactions,
hypersensitivity reactions of types II, III and IV will not be
further discussed in detail.
Fungal type I allergy is induced by a large number of fun-
gal genera, the most important ones belonging to the asc-
omycota followed by basidiomycota and zygomycota (23).
Clinically, the IgE-mediated sensitization to fungal allergens
can manifest as allergic rhinitis and rhinosinusitis (35), aller-
gic asthma (36) and atopic dermatitis (37).
Allergic rhinitis and rhinosinusitis
Allergic rhinitis affects up to 40% of the population and
results in nasal itching, congestion, sneezing and clear rhinor-
rhea. Allergic rhinitis causes extranasal adverse effects includ-
ing decreased quality of life, decreased sleep quality and
obstructive sleep apnoea (38). However, epidemiologic studies
have failed to demonstrate a direct relationship between fun-
gal allergy and allergic rhinitis via either outdoor or indoor
exposure. Fungal allergy is clearly linked to a subset of
chronic rhinosinusitis (CRS) known as allergic fungal rhinosi-
nusitis (AFRS) (39). In the patient’s mucus, fungal hyphae
are detectable and patients show coetaneous hypersensitivity
to specific fungal allergens along with specific IgE and IgG
antibodies against the sensitizing fungus and an increased
total serum IgE level (40). Immunologically, allergic fungal
rhinosinusitis is a mixed type I, type III and type IV allergic
reaction.
Allergic asthma
There is compelling evidence that fungal allergy is associated
with severe asthma (41). Although the precise prevalence of
fugal sensitivity is unclear, recent estimates indicate that
24.6 million people in the United States suffer from asthma
(42). Depending on the definition, about 10–20% of these
patients might be classified as subjects suffering from severe
asthma, and in this group, 30–70% can be expected to be
sensitized to at least one fungal species (Table 1). Extrapolat-
ing this figure to the industrialized countries, we have to
assume that several millions of asthmatic patients are affected
by fungal allergy (27). However, with exception of special
cases such as workplace exposure or allergic bronchopulmo-
nary aspergillosis (ABPA), which are well documented, the
contribution of fungal sensitization to the severity of asthma
remains to be investigated.
Allergic bronchopulmonary aspergillosis and related
conditions
ABPA is commonly caused by Aspergillus fumigatus, a ubiq-
uitous mould frequently found indoors and outdoors. The
syndrome is characterized by exacerbations of asthma, recur-
rent transient chest radiographic infiltrates, peripheral and
pulmonary eosinophilia, and development of bronchiectasis
(43). Although originally considered a rarity (44), ABPA is
currently recognized as a serious disease affecting approxi-
mately 3% of asthmatic patients (41) and up to 10% of
patients with cystic fibrosis (45). However, in asthmatic and
CF patients sensitized to A. fumigatus, the incidence of
ABPA might be much higher ranging from 15 to 35% (46,
47). Immunologically, ABPA is a mixed type I, type III and
type IV hypersensitivity lung disease induced by bronchial
colonization with A. fumigatus causing symptoms ranging
from asthma exacerbation to fatal destruction of the lung
(48). ABPA as a syndrome suspected from clinical signs is
not trivial to be diagnosed, and several criteria that are, how-
ever, not specific for the disease have been suggested (45, 49,
50). Therefore, serological findings showing sensitization to
A. fumigatus are essential diagnostic tools to confirm or
exclude the disease. ABPA is a disease with a high risk of the
development of irreversible end-stage fibrosis, and therefore,
it is recommended to rule out sensitization to A. fumigatus in
Table 2 Classification of hypersensitivity reactions*
Category†
Humoral
response
Soluble
mediators
Time
course Cellular response Clinical examples Fungal diseases
Type I IgE Histamine,
leukotrienes
Minutes Smooth muscle constriction,
eosinophil infiltration
Rhinitis, allergic asthma
(143)
Allergic rhinitis (39)
Allergic asthma (42, 48)
ABPA (133–137)
ABPM (23)
Type II IgG, IgM Complement 1–24 h Neutrophil activation and
lysis of target cells
Autoimmunity(144) Unknown
Type III IgG, IgM Complement 1–24 h Infiltration and activation of
granulocytes
Rheumatoid arthritis (145) Hypersensitivity
pneumonitis‡
Aspergilloma (137)
Type IV T cells Lymphokines 2–3 days T-cell and macrophage
activation
Tuberculosis, contact
dermatitis (146, 147)
ABPA (133–137)
Hypersensitivity
pneumonitis (135, 136)
*Modified from references (33) and (34).
†Most of the IgE-associated fungal diseases are mixed forms involving combinations of types I, III and IV hypersensitivity reactions (23).
‡Also termed extrinsic allergic alveolitis (137).
Allergy 69 (2014) 176–185 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd178
Fungal allergens Crameri et al.
4. all asthmatic patients (51). In this regard, recombinant aller-
gens might contribute to a more reliable diagnosis of ABPA.
Other fungi, including Candida, Penicillium and Curvularia
species, are occasionally responsible for a similar syndrome
termed ‘allergic bronchopulmonary mycosis’ (ABPM) (52).
The endotype classification of asthma syndromes proposed
recently (53) also include ABPM. Like ABPA, the character-
istics of ABPM include severe asthma, blood and pulmonary
eosinophilia, marked increased levels of total and allergen-
specific IgE, bronchiectasis and mould colonization of the
airways. The term ‘severe asthma associated with fungal sen-
sitivity’ (SAFS) has been introduced to illustrate the high rate
of fungal sensitivity in patients with severe asthma (54).
Because of the ambiguity in diagnostic criteria, SAFS is
currently more a diagnosis by exclusion than a diagnosis of a
specific disease entity (55).
Atopic dermatitis
Atopic dermatitis (AD) is a chronic relapsing, highly pruritic
inflammation of the skin with a worldwide prevalence of
10–20% in children and of 1–3% in adults (22, 56). The
pathophysiology of AD, also called atopic eczema, is com-
plex and not fully understood (57). Recently, Malassezia
sympodialis, a lipophilic yeast colonizing the skin of both AD
and healthy individuals, has been shown to induce IgE-medi-
ated sensitization exclusively in patients suffering from AD
(22). The main reason for this specific sensitization may be
the disrupted skin barrier facilitating allergen uptake, which
may contribute to the perpetuation of the disease (58). Of
special interest in this regard are cross-reactivity reactions
between M. sympodialis allergens sharing a high degree of
sequence identity to human proteins (8, 28). It has been con-
vincingly shown, both, in vitro and in vivo that Mala s 11,
the M. sympodialis manganese-dependant superoxide dismu-
tase, sharing 50% sequence homology with the human
enzyme (59), can elicit strong humoral- and T-cell-mediated
immune reactions in a subset of AD patients (60). These
reactions have been traced back to structural similarities
between the two proteins (59) and studied in detail at the T-
cell level (61). However, the phenomenon of autoreactivity to
human proteins in AD patients is not limited to Mala s 11
and human superoxide dismutase as recently shown in studies
investigating Mala s 13 and human thioredoxin (62, 63) and
can be extended to a whole array of human proteins (64).
whether sensitization to other fungi, except Saccharomyces
cerevisiae, which shows a significant correlation between a
positive skin prick test and AD (65), is involved in the patho-
genesis of the disease remains to be determined.
Fungal allergens
The list of fungal allergens officially approved by the
Nomenclature Subcommittee of the International Union of
Immunological Societies (IUIS; www.allergen.org) spans 105
iso-allergens and variants from 25 fungal species belonging to
the Ascomycota and Basidiomycota phyla (20). However, the
number of fungal proteins able to elicit type I hypersensitivity
reactions described in the literature is much longer, even if
many of these allergens are poorly characterized. A recent
catalogue of the fungal allergens described (23) lists 174 aller-
gens for the genus Ascomycota and 30 for the genus Basidi-
omycota. However, this list does not include many fungal
allergens, which have been only partially characterized in
terms of primary sequence. For example, it has been shown
by high-throughput screening technology that A. fumigatus,
perhaps the most important allergenic mould, is able to
produce at least eighty-one different IgE-binding proteins
(66). The same approach applied to phage surface display
libraries of Cladosporium herbarum, Coprinus comatus and
Malassezia furfur yielded at last 28, 37 and 27 different
clones, respectively, displaying IgE-binding proteins (67).
These few examples clearly show that the repertoire of fungal
allergens is far from being completely elucidated. Besides spe-
cies-specific allergens such as Asp f 1 and Alt a 1, which are
limited to genera or species (68), databases of allergen
sequences compiled and used to search fungal proteomes
revealed that some highly homologous allergen orthologue
classes and allergen epitopes are ubiquitous in all fungi (69).
It seems likely that many of these protein orthologues are
potential allergens or at last capable of cross-reacting as pro-
teins showing a high degree of sequence homology are likely
cross-reactive (70). Cross-reactivity between homologous
fungal allergens has been demonstrated in many cases
between phylogenetically close (71, 72) and even distant spe-
cies such as Candida boidiini and A. fumigatus (73). Some
examples of major and cross-reactive fungal allergens are
given in Table 3. Although the clinical relevance of cross-
reactivity between fungal allergens remains to be investigated
in more detail (7), the phenomenon is well understood at a
scientific level. The availability of high-resolution three-
dimensional structures of eight fungal allergens (74–81)
allowed researchers to understand in details the structural
basis of cross-reactivity (70), to homology model unsolved
structures of fungal allergens (59, 82–84) and to test the cor-
rectness of the hypotheses by site-directed mutagenesis and
immunological investigations (59,85). Moreover, serologic
studies involving recombinant A. fumigatus allergens contrib-
uted to corroborate a clinical diagnosis of ABPA by the dis-
covery of disease-specific allergens (86, 87). In contrast to
secreted allergens, which are recognized by serum IgE of
A. fumigatus-sensitized individuals with or without ABPA,
some nonsecreted allergens are predominantly recognized by
serum IgE of ABPA patients (45, 86–89). This differential
immunological response is probably due to the fact that
ABPA patients have or had the fungus growing in the lung
(90). Therefore, as a result of fungal damage due to cellular
defence mechanisms, they become more strongly exposed to
nonsecreted proteins than A. fumigatus-allergic individuals,
which mainly recognize environmental fungal allergens (91).
The diagnosis of fungal allergy: an unsolved medical
need
As already mentioned and confirmed in a recent study
supported by the European community (GA2
LEN (92)), the
Allergy 69 (2014) 176–185 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 179
Crameri et al. Fungal allergens
5. incidence of fungal sensitization is high (Table 1) and clini-
cally relevant. However, the problems related to the in vitro
and in vivo diagnosis of fungal and other allergies are far
from being solved (93). Of course any in vivo diagnosis of
allergy based on skin tests as well as any in vitro diagnosis of
allergy based on the determination of allergen-specific IgE
depends on the quality of the material used for testing.
Although standardized extracts approved by the FDA are
available for some allergenic sources (94, 95), no fungal
extracts have been approved to date. This is not astonishing
because, in contrast to pollens or insect venoms, which repre-
sent allergenic sources more or less ‘standardized’ by nature
as a feature of their biological function, fungi as allergenic
source are extremely complex. Problems encountered in the
standardization of fungal extracts derive from different pat-
terns of allergens produced by different clinical isolates (96),
batch to batch variations (97), time-dependent liberation of
IgE-binding components during fungal growth (98), instabil-
ity of the extracts due to protease content (99), culture condi-
tions and medium used to grow the fungus and, of course,
the extraction procedures (100). Moreover, fungi produce
cell-bound, secreted and intracellular allergens (101), making
it impossible to produce consistent extracts containing the
three types of allergens in a single run. Therefore, even com-
mercial extracts for skin tests provided by different suppliers
deliver discrepant results (102). In clinical routine, fungal sen-
sitization is normally assessed in vitro by determination of
serum IgE levels with ImmunoCAPs, still considered the
‘gold standard’ for the in vitro diagnosis of allergy (103).
Unfortunately, the ImmunoCAP manufacturer does not pro-
vide the extracts used to produce the in vitro test system as
skin test solution, hampering a direct comparison of the skin
test reactivity of a commercial extract with the serum IgE
levels determined with the corresponding ImmunoCAP. This
would be extremely important because (fungal) extracts con-
tain the so-called cross-reactive carbohydrate determinants to
which about 20% or more of the sensitized patients generate
specific antiglycan IgE (104). Even though antibody-binding
glycoproteins are widespread in many extracts and therefore
detected by in vitro diagnostic tests, cross-reactive carbohy-
drate determinants do not appear to cause clinical symptoms
in most, if not all, patients and can thus be considered as
clinically irrelevant allergens (104). In fact, comparisons of
skin test and serology obtained with recombinant allergens
produced in E. coli, and thus lacking post-translational modi-
fications, correlate fairly well (105) in contrast to those
obtained with fungal extracts (106). Moreover, the clinical
history that represents one of the most important diagnostic
criteria for an allergy is difficult to reconstruct for patients
with a fungal allergy. In contrast to other allergies such as
seasonal pollen-derived allergies, most patients sensitized to
fungi are not aware of the source of exposure and can only
report that the symptoms are more or less perennial. Techno-
logical developments in allergen cloning and microarrays
(107–110), together with the proved superior diagnostic per-
formance of recombinant allergens compared with extracts
(111–113), might contribute to a more specific and sensitive
component-resolved diagnosis of allergy (114–116) in the
future. However, due to the high number of different aller-
gens produced by fungi, it is unlikely that a solution for this
urgent medical need will be reached in the near future, and
the first recombinant fungal allergens (Alt a 1, Asp f 1, Asp f
2, Asp f 3 and Asp f 4) immobilized in ImmunoCAPs are
now commercially available from Thermo scientific (www.
phadia.com).
The treatment of fungal allergy
As for all other allergies, avoiding exposure is still the best
treatment for these diseases. Because fungi are ubiquitous in
Table 3 Major fungal allergens with or without cross-reactivity
Allergen Genus
Accession
Number
MW
(kDa) Biological Function Cross-reactive with* Ref.
Alt a 1 Alternaria alternata U82633 30 Unknown NF (69)
Asp f 1 Aspergillus fumigatus M83781 18 Ribotoxin NF (68, 69, 148)
Asp f 3 A. fumigatus U58050 19 Peroxisomal protein Candida boidiini (73)
Asp f 11 A. fumigatus AJ006689 24 Cyclophylin Asp f 27, Mala s 6, Cyclopylins of
Candida albicans, Saccharomyces
cerevisiae, Homo sapiens
(75, 149)
Asp f 29 A. fumigatus AJ937745 13 Thioredoxin Asp f 28, Mala s 13, H. sapiens
thioredoxin
(72, 76)
Asp f 34 A. fumigatus AM496018 20 Phi A cell wall protein NF (150)
Cla h 8 Cladosporium herbarum AJ181916 28 Mannitol dehydrogenase Alt a 8 (151)
Pen o 18 Penicillium oxalicum AF243425 34 Vacuolar serine protease Cla h 18, Asp f 18 (152)
Mals s 6 Malassezia sympodialis AJ011956 17 Cyclophilin Asp f 11, Asp f 27, Asp f 28,
H. sapiens cyclophilin
(75)
Mala s 11 M. sympodialis AJ548421 23 MnSOD Asp f 6, H. sapiens MnSOD (60, 74, 85)
*NF: not found.
These allergens are considered species specific and unique (69). Many phylogenetically highly conserved allergens react also with their
human counterpart.
Allergy 69 (2014) 176–185 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd180
Fungal allergens Crameri et al.
6. our environment, a complete avoidance of exposure is not
feasible. However, reduction in asthma morbidity following
interventions for improving indoor air quality and remedia-
tion of moisture incursion have been demonstrated (117).
Of course, allergen-specific immunotherapy is currently the
only treatment capable of curing allergic diseases (118) and
has been used in clinical practice for more than hundred
years (119). A limited number of controlled immunotherapy
trials with Alternaria alternata and C. herbarum extracts have
indicated some clinical benefit (120); however, large-scale,
double-blind, placebo-controlled studies of fungal allergen-
specific immunotherapy are lacking. In general, immunother-
apy for fungal allergy is not recommended mainly because of
the lack of standardized therapeutic reagents (121).
As the majority of the patients suffering from fungal sensi-
tization are severe asthmatics, inhaled corticosteroids and fre-
quent courses of oral corticosteroids are used to control the
asthma (122, 123) and contribute to alleviate the allergic
symptoms (124). Severe conditions such as ABPA, ABPM or
SAFS exacerbations are best treated with oral steroids over
3–6 weeks (123) corroborated by inhaled corticosteroids.
Although there are conflicting data concerning the clinical
utility of inhaled corticosteroids in reducing exacerbation fre-
quency, they are an important therapeutic intervention to
control the worst symptoms of underlying asthma (125, 126),
but with the well-known adverse side-effects (127). An alter-
native or adjunctive strategy in the treatment of these dis-
eases is to reduce or clear the lung of fungal colonization by
antifungal agents (128). Although some placebo-controlled
randomized studies demonstrated the benefit of itraconazole
therapy for ABPA (129, 130), the adjuvant role of antifungal
treatment in severe forms of fungal allergy should be investi-
gated in more detail with special attention to the effects on
corticosteroid dose, frequency of exacerbations, quality of
life, immunological changes and side-effects.
Other diseases associated with fungal exposure
Fungi play an important role also in other important diseases
associated with fungal exposure, although not primarily IgE
mediated. As this review is focused on fungal allergy, these
diseases are only briefly mentioned here. The most dangerous
diseases caused by fungi are invasive mycoses (131, 132).
Most opportunistic mycoses occur in individuals with con-
genital or acquired immunodeficiency; morbidity and mortal-
ity rates are high, and prevention, diagnosis and treatment of
these infections remain difficult (133). Less harmful but wide-
spread in the population are fungal infections of the skin.
Superficial mycoses are characterized by invasion restricted
to the stratus corneum and therefore usually not associated
with inflammatory or immune responses of the host (134).
Other diseases caused by fungi partially are related to expo-
sure at the workplace (135). Included in this disease group
are hypersensitivity pneumonitis also called extrinsic allergic
alveolitis (136), farmer’s lung, bagassosis and mushroom
worker’s lung, which result from occupational exposure to
thermophilic actinomycetes present in hay, bagasse and
mushroom compost, respectively (137).
Conclusions
The impact of fungal allergy on human health, especially in
patients suffering from asthma or cystic fibrosis, and an
emerging role of Malassezia sensitization in the exacerbation
of atopic dermatitis have been clearly demonstrated during
the past years. There is no doubt that fungi are involved in
many allergic disorders and, as best documented example, in
ABPA.
Acknowledgments
The laboratory of the author is supported by the Swiss
National Science Foundation Grant Nos 320030_149978 and
32NM30_136032/1 (EuroNanoMed) and by the European
Community’s Seventh Framework Program [FP7-2007-2013]
under grant agreement no. HEALTH-F2-2010-260338
‘ALLFUN’.
Conflicts of interest
The authors declare no conflicts of interest.
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